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Glycation, a non-enzymatic modification of lysine and arginine residues by reducing sugars or reactive dicarbonyls, may disrupt proteostasis and trigger pathology. Here, we investigated how methylglyoxal (MGO)- and ribose-mediated glycation influence aSyn aggregation, neuroinflammation, and detoxification pathways. Using SH-SY5Y cells, primary neurons, primary microglia and MGO-injected aSyn transgenic mice, we found that MGO-glycated aSyn promotes PD associated pathological features, including pS129-positive aSyn aggregates, neuroinflammation, and impairment of the glyoxalase detoxification pathway. Ribose-glycated aSyn, while immunogenic, exerts limited effects on aggregation and seeding. Both glycated species activates microglia and upregulate pro-inflammatory markers. We further developed a novel antibody specific for MGO-glycated aSyn, which selectively detects Lewy body\u2013like deposits in dementia with Lewy bodies (DLB) tissue and MGO-injected mice. These findings implicate MGO-glycation in PD-T2DM comorbidity.<\/jats:p>","DOI":"10.1038\/s41531-025-01159-w","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T13:28:47Z","timestamp":1761226127000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Glycation of alpha-synuclein enhances aggregation and neuroinflammatory responses"],"prefix":"10.1038","volume":"11","author":[{"given":"Eftychia","family":"Vasili","sequence":"first","affiliation":[]},{"given":"Annekatrin","family":"K\u00f6nig","sequence":"additional","affiliation":[]},{"given":"Mohammed","family":"Al-Azzani","sequence":"additional","affiliation":[]},{"given":"Clara","family":"Bosbach","sequence":"additional","affiliation":[]},{"given":"Luisa Maria","family":"Gatzemeier","sequence":"additional","affiliation":[]},{"given":"Searlait","family":"Thom","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Cheg\u00e3o","sequence":"additional","affiliation":[]},{"given":"Hugo","family":"Vicente Miranda","sequence":"additional","affiliation":[]},{"given":"Claudia","family":"Steinem","sequence":"additional","affiliation":[]},{"given":"Daniel","family":"Erskine","sequence":"additional","affiliation":[]},{"given":"Tiago F.","family":"Outeiro","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,10,23]]},"reference":[{"key":"1159_CR1","unstructured":"Maillard, L. 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